Abstract
Dietary habits and vascular risk factors promote both Alzheimer's disease and cognitive impairment caused by vascular factors. Furthermore, accumulation of hyperphosphorylated tau, a microtubule associated protein and a hallmark of Alzheimer's pathology, is also linked to vascular cognitive impairment. In mice, a salt-rich diet leads to cognitive dysfunction associated with a nitric oxide deficit in cerebral endothelial cells and cerebral hypoperfusion. Here we report that dietary salt induces tau hyperphosphorylation followed by cognitive dysfunction, effects prevented by restoring endothelial nitric oxide production. The nitric oxide deficiency reduces neuronal calpain nitrosylation resulting in enzyme activation, which, in turn, leads to tau phosphorylation by activating cyclin dependent kinase-5. Salt-induced cognitive impairment is not observed in tau-null mice or in mice treated with anti-tau antibodies, despite persistent cerebral hypoperfusion and neurovascular dysfunction. These findings unveil a causal link between dietary salt, endothelial dysfunction and tau pathology, independent of hemodynamic insufficiency. Avoiding excessive salt intake and maintaining vascular health may help stave off vascular and neurodegenerative pathologies underlying late-life dementia.
